Ischemia occurs when there is an imbalance between oxygen supply and demand, leading to an insufficient supply of oxygen to a tissue or organ. Ischemia often occurs as the result of the formation of a blood clot (thrombus) in a vessel which then obstructs the flow of blood in the vessel.
In ischemic strokes an occlusive thrombus forms in one of the vessels of the brain. Ischemic stroke may be thrombotic or embolic in origin. In a thrombotic stroke, a blood clot develops in a vessel already narrowed by atherosclerosis. In an embolic stroke, a clot forms elsewhere in the body and travels through the circulatory system to the brain.
Lacunar strokes, which are strokes due to the blockage of small arteries in the brain, may be thrombotic or embolic in origin. In some cases lacunar strokes can also arise from causes other than arteriosclerosis, such as lipohyalinosis.
The likelihood of a clot forming in a vessel is determined by the balance between the coagulation cascade, which favours clot formation, and the fibrinolytic system, which favours lysis of the clot. Both the coagulation cascade and the fibrinolytic system involve a complex cascade of proteolytic events. The final effector molecule of the coagulation cascade is the serine protease thrombin, which cleaves fibrinogen to form the fibrin clot. The final effector molecule of the fibrinolytic system is the serine proteinase plasmin, which cleaves fibrin into soluble degradation products.
Tissue plasminogen activator (tPA) plays a critical role in the fibrinolytic system. tPA catalyses the conversion of the inactive precursor plasminogen into the active proteinase plasmin. As such, tPA is the primary mediator of intravascular fibrinolysis preventing thrombosis. The secretion of tPA by endothelial cells is regulated by two mechanisms: (a) an acute release of local tPA that is precipitated by vascular injury and occurs within seconds to minutes and (b) a long-term basal secretion rate that is determined by the chronic activation of the fibrinolytic system and is responsible for the changes in the circulating plasma level of tPA. The circulating tPA activity is also attenuated through the formation of an irreversible complex with plasminogen activator inhibitor-1. A variety of stimuli such as venous occlusion, exercise, or injection of vasoactive substances are known to acutely increase plasma levels of t-PA by stimulating release of tPA.
Activation of the fibrinolytic system does not necessarily correlate with a reduced probability of suffering an ischemic stroke. Indeed, in some cases prolonged activation of the fibrinolytic defense system appears to precede a stroke event by several years.
There is currently very little information regarding the importance that genetic factors play in the development of diseases and conditions associated with occlusive thrombosis, and in particular, the genetic factors that play a role in ischemic stroke. As such, there is a need for methods of identifying subjects that may be susceptible to occlusive thrombosis, including methods for identifying subjects that are susceptible to ischemic stroke.
The present invention relates to methods of identifying subjects predisposed to ischemic stroke by identifying a mutation in the subject that reduces the rate of release of tissue plasminogen activator. In particular, the present invention relates to the identification that the presence of a specific polymorphism in the upstream region of the tPA gene is associated with ischemic stroke. This polymorphism is associated with a reduced rate of release of tPA. Throughout this specification reference may be made to documents for the purpose of describing various aspects of the invention. However, no admission is made that any reference cited in this specification constitutes prior art. In particular, it will be understood that the reference to any document herein does not constitute an admission that any of these documents forms part of the common general knowledge in the art in Australia or in any other country. The discussion of the references states what their authors assert, and the applicant reserves the right to challenge the accuracy and pertinency of any of the documents cited herein.